Case Studies: Application o

Pharmacokinetic Modeling 

Inform Water Monitoring Inform Water Monitoring Monitoring

Presentation to the FIFRA Scientific Advisory P

July 26-29, 2011

Chester Rodriguez Chester Rodriguez

Nelson Thurman

USEPA Office of Pesticide Programs USEPA Office of Pesticide Programs
Outline

• How did we get here? (C. Rodriguez)• P d i i d i (C R d i 

Proposed water monitoring durations (C. Rodri

• Estimating drinking water exposure from monisampled at weekly intervals (N Thurman) sampled at weekly intervals (N. Thurman)

• Estimates for 1995 Maumee R• Estimates for 2007 MO-01

• Estimating human plasma AUC from drinking exposures (C. Rodriguez)

• Estimates for 1995 Maumee R• Estimates for 2007 MO-01

• Summary (C. Rodriguez)

Summary (C. Rodriguez)
1

22

ing Hormone m (ng/ml)

Repe

468

1 mg/kg bw ATRA3 mg/kg bw ATRA

7 mg/kg bw ATRA10 mg/kg bw ATRA

ma Triazines (mg/L)

PK Profile of Radiolabeled Triazines

1

 Leutinizi

Serum

0 24 48 72 96 120 144 168 192 216 240 264 288

024

start of dosing pseudo steady state dosing stopped

Radiolabeled Plas time (hrs)m

024

eled triazines(ppm))

Linear Elimina

100012501500 y= 13.0x - 8.57

R2 = 0.994

daily

e AUC

h)

AUC Scales with Atrazine Dose

(Dose rate) AUC forrat LH t 48 96 144 

-4-2

0

t

ln (Plasma radiolabe

0 20 40 60 80 100

0

250500750

ATRA dose (mg/kg/day)

pseudod

steady stat

(mg/L-(Dose rate) rat Vdssrat * kel rat AUC forrat LH attenuation =

Plasma Triazines

(Cp, mg/L) 

kel (hr‐1) Triazines

eliminated

Atrazine

(mg) Vdss(L)

One‐compartmentlinear model

Av

AUC =

(Dose rate) human

Vdss human * kel human

Dose rate

WatWat
Range of Windows of Expo

• 4, 14, and 28 days• 4-day duration:

• Accumulation of plasma Accumulation of plasma triazines triazines to steady state seems 

to steady state seems 

to maximal LH attenuation

• Based on a constant dose level and frequency, time to s

the rat is 4 days the rat is

4 days

• Length of the rat estrous cycle

• 28-day duration:

• Within the allometrically scaled time range for adult hum

to reach steady state based on a constant dose level and 

• 28 da

y gg 

s also the avera

ge len

gth of the human menstrua

• 14-day duration:

• Serves as midpoint given the other durations• Reasonable to include given that human exposure is ne

constant dose level nor constant frequency
Estimating Drinking Water Exposu

Monitoring Monitoring Sampled at Weekly In

Monitoring Sampled Sampled at Weekly In

In

• Used 2 monitoring data sets with daily s

Used

2 monitoring data sets with daily s

during the high use/runoff period

• Simulated sampling at 7-day intervals from 

• Used geostatistical methods to develop 

variogram model that captures the cova

monitoring data over time based on 7 monitoring data over time based on

7

-da

sampling intervals

• Ran 1,000 conditional simulations of the 

covari d l t ti t d il ti 

iance mo

d

el to estima

te 

d

aily time 

from the 7-day sampling intervals

• Bracketed the 5th

-95th

• Bracketed the

5

-95 percentiles of the percentiles of the

conditional simulations from the 7-day in
Estimates for 2007 MO

-01 Sam

100 Weekly Intervals

D il Ti S i Si 95th %il

100

Si 95th %il

4 Day Average

60708090

ion, ug/L

D

aily Time 

Series Si

m 95th %ile

Sim 5th %ileActual

60708090

tion, ug/L

Si

m 95th %ile 4-Day Average

Sim 5th %ileActual

2030405060

Atrazine Concentrati 2030405060

Atrazine Concentra

0

10

20

91 98 105 112 119 126 133 140 147 154 161 168 175 182 189

A

Julian Day

0

10

20

91 98 105 112 119 126 133 140 147 15

Julian Day

100

Sim 95th %ile 14-Day Averages 100 Sim 95th %ile 28 Day Averag

60708090

ation, ug/L

Sim 95th %ile 14-Day AveragesSim 5th %ileActual

60708090

ation, ug/L

Sim 95th %ile 28-Day AveragSim 5th %ileActual

2030405060

Atrazine Concentra

2030405060

Atrazine Concentra

0

10

20

91 98 105 112 119 126 133 140 147 154 161 168 175 182 189

Julian Day

0

10

20

91 98 105 112 119 126 133 140 147 15

Julian Day
Estimates for 1995 Maumee 

Sampled at Weekly Interv

Estimates for 1995 Maumee 

16 Sampled at Weekly Interv

D il Ti S i Si 95th %il 16 Si 95th %il

4 Day Averages p y

101214

on, ug/L

D

aily Time 

Series Si

m 95th %ile

Sim 5th %ileActual

101214

ation, ug/L

Si

m 95th %ile 4-Day Averages

Sim 5th %ileActual

468

Atrazine Concentrati

468

Atrazine Concentra

02

91 98 105 112 119 126 133 140 147 154 161 168 175 182 189

A

Julian Day

02

91 98 105 112 119 126 133 140 147 154 

Julian Day

16

Sim 95th %ile 14-Day Averages

16

Sim 95th %ile 28-Day Averag

101214

ation, ug/L

Sim 95th %ile 14-Day AveragesSim 5th %ileActual

101214

ation, ug/L

28-Day Averag

Sim 5th %ileActual

468

Atrazine Concentra

468

Atrazine Concentra

02

91 98 105 112 119 126 133 140 147 154 161 168 175 182 189

Julian Day

02

91 98 105 112 119 126 133 140 147 15

Julian Day
Estimating Human Plasma AUC 

Atrazine Concentrations in Dri

Concentrations in Dri

Water

Atrazine Concentrations in Dri

Water

[atrazine levels]ave (μg/L) x water consum

kel (hr-1) x Vdss (L)

=

Human Plasma 

Ave. Daily AUC

Rat Plasma PoD AUC for LH atte

Predicted human plasma ave. d

Internal Measure

Margin of Exposure

=
Rolling Average Human Plasma AUC 

for the 2007 MO-01 Monitoring D

MO-01: daily sampling

0.25

actual (daily sampling)

BMDL AUC/100x

g/L)*h)

MO-01: 4-d rolling avera

0.25

actual 4-d rolling ave

g/L)*h)

0 050.100.150.20 actual (daily sampling)

Sim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)

BMDL AUC/300x

plasma AUC ((mg 0 05 0.10 0.15 0.20 actual 4 d rolling ave Sim 95%ile (weekly sampling) Sim 5%ile (weekly sampling) 

plasma AUC ((mg

100 110 120 130 140 150 160 170 180 190 200

0.000.05

Julian Day

human p 100 110 120 130 140 150 160 170 

0.000.05

Julian Days

 human 

MO-01: 14-d rolling averages

0.25

actual (14-d rollin

g ave)

BMDL AUC/100x

L)*h)

MO-01: 28-d rolling av

0.25 

L)*h)

0.100.150.20

( g)

Sim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)

BMDL AUC/300x

lasma AUC ((mg/ 0.10 0.15 0.20 Sim95%ile (weekly sampling) Sim 5%ile (weekly sampling) actual (28-d rolling ave) 

lasma AUC ((mg/

100 110 120 130 140 150 160 170 180 190 200

0.000.05

Julian Days

human pl 90 100 110 120 130 140 150 16

0.00 0.05

Julian Days

human pl
Estimates of Rolling Human Pl

Average Daily AUC Values

Maumee 95: Daily Sampling

0 150.200.25

actual (daily sampling)

BMDL AUC/100x

((mg/L)*h)

Maumee 95: 4-day rol

0.200.25

actual 4-day rolling ave.

((mg/L)*h) Sim 95%ile (weekly sampling)

0 000.050.100.15 Sim 95%ile (weekly sampling)

Sim 5%ile (weekly sampling)

BMDL AUC/300x

uman plasma AUC 0 00 0.05 0.10 0.15 

Sim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)

uman plasma AUC 

100 110 120 130 140 150 160 170 180 190 200

0.00

Julian Day

Hu 100 110 120 130 140 150 16

0.00

Julian Days

Hu

Maumee 95: 14-d rolling averages

0.150.200.25

actual 14-d rolling ave Sim95%ile (weekly sampling)Sim5%ile (weekly sampling)

BMDL AUC/100x

UC ((mg/L)*h) Maumee 95: 28-d rolli

0.15 0.20 0.25 Sim95%ile (weekly samplin

 Sim5%ile (weekly samplingactual 28-d rolling ave 

UC ((mg/L)*h)

100 110 120 130 140 150 160 170 180 190 200

0.000.050.10

Sim5%ile (weekly sampling)

BMDL AUC/300x

Human plasma AU 100 110 120 130 140 150 160 

0.00 0.05 0.10 

Human plasma AU

Julian Days

100 110 120 130 140 150 160 

Jilian Days
Summary of Pharmacokinetic M

to Inform Water Monitorin

• Based on an internal dose metric (AUC) c

with temporality of LH attenuation with temporality of LH attenuation

• AUC accounts for magnitude and duration 

ex

posure

• One compartment model: best available sc

the absence of a fully calibrated and evalu

PBPK model

• One compartment model accounts for bod

distribution and plasma clearance

• The higher the water levels, the higher the 

predicted human plasma levels for a given (linear relationship)